Submitted August 20, 2007
Accepted October 31, 2007
Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI
Manojkumar Valiyaveettil, Niladri Kar, Mohammad Z Ashraf, Tatiana V Byzova, Maria Febbraio, and Eugene A Podrez*
Department of Molecular Cadiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
* Corresponding author; email: podreze{at}ccf.org.
Numerous studies have reported the presence of oxidatively modified HDL (OxHDL) within the intima of atheromatous plaques as well as in plasma; however, its role in the pathogenesis of thrombotic disease is not established. We now report that OxHDL but not native HDL is a potent inhibitor of platelet activation and aggregation induced by physiological agonists. This anti-thrombotic effect was concentration and time dependent and positively correlated with the degree of lipoprotein oxidation. Oxidized lipoproteins are known ligands for scavenger receptors type-B, CD36 and SR-BI, both of which are expressed on platelets. Studies using murine CD36-/- or SR-BI-/- platelets demonstrated that the anti-thrombotic activity of OxHDL depends on platelet SR-BI but not CD36. Binding to SR-BI was required since pre-incubation of human and murine platelets with anti-SR-BI blocking antibody abrogated the inhibitory effect of OxHDL. Agonist induced aggregation of platelets from eNOS, Akt-1 and Akt-2 -/- mice was inhibited by OxHDL to the same degree as platelets from WT mice indicating that the OxHDL effect is mediated by pathway different from the eNOS/Akt pathway. These novel findings suggest that contrary to the pro-thrombotic activity of oxidized-LDL, HDL upon oxidation acquires anti-thrombotic activity that depends on platelet SR-BI.
